Thorax (1976), 31, 356.

Necrotizing 'sarcoidal' angiitis and granulomatosisof the lung

J. G. STEPHEN, M. V. BRAIMBRIDGE,B. CORRIN, S. P. WILKINSON, D. DAY, and

W. F. WHIMSTER

St. Thomas' Hospital and King's College Hospital, London

Stephen, J. G., Braimbridge, M. V., Corrin, B., Wilkinson, S. P., Day, D., and WhimsterW. F. (1976). Thorax, 31, 356-360. Necrotizing 'sarcoidal' angiitis and granulomatosisof the lung. A case of necrotizing sarcoid angiitis and granulomatosis (NSG) presentingas a peripheral lung 'tumour' in a 63-year-old man is recorded, and the clinical andpathological features are compared with those of Liebow's original cases. Resectionmay be avoided if the diagnosis is made by biopsy as the disease is possibly steroidresponsive and the prognosis appears favourable. The aetiology is obscure but an

immune disturbance is suspected.

Liebow (1973) has recently defined five forms ofpulmonary angiitis and granulomatosis not pro-duced by known infec:ious agents or associatedwith rheumatoid disease. These are: (1) theclassical form of Wegener's disease in whichgranulomatosis in the lung is associated withsimilar lesions in the upper respiratory tract andelsewhere together with glomerulonephritis(Wegener, 1936, 1939); (2) Wegener-type lesionslimited to the lung (Carrington and Liebow, 1966);(3) lymphomatoid granulomatosis (Liebow, Car-rington, and Friedman, 1972); (4) necrotizing'sarcoid' angiitis and granulomatosis (NSG), and(5) bronchocentric granulomatosis (Katzenstein,Liebow, and Friedman, 1975). While the firstthree types are well documented, NSG andbronchocentric granulomatosis possibly representpreviously unrecognized or even new entities. Cer-tainly most practitioners will be unfamiliar withthese diseases. This report describes a case ofNSG which presented recently as a peripherallung mass initially thought to be a neoplasm.

CASE REPORT

A 63-year-old underground station master pre-sented in March 1974 with an 18-month his'oryof episodic tightness in the chest, mainly onexertion. He had a morning cough with whitishsputum but was dyspnoeic only on severe exertion.He was otherwise well and had not lost weight.

There was no history of allergy or exposure toindustrial pulmonary hazards. He smoked 20cigarettes per day. A urinary tract infection hadbeen treated in 1967, at which time chest radio-graphy and pyelography were normal. In 1971 hedeveloped erythematous skin lesions on the legs,and biopsy of these showed atrophy of the dermisbut no arteritis, necrosis, inflammation or scar-ring. These lesions subsequently resolved withapplication of a steroid cream.On examination he was a fit-looking slightly

obese man with no cyanosis or clubbing. No en-larged lymph nodes were palpable. The bloodpressure was 135/75 mmHg and the pulse andheart sounds were normal. Widespread wheezeswere present over both lungs. There were noabnormal signs in the abdomen. Investigationsshowed: Hb 16-4 g/dl; WBC 8600/mm3 with67% neutrophils, 26% lymphocytes, 5% mono-cytes, and 2% eosinophils; ESR 8 mm/h; plateletsnormal. Serum sodium was 134 mmol/l, potassium3.7 mmol/l, bicarbonate 21 mmol/l, and bloodurea 6-8 mmol/l.

Chest radiography (Fig. 1) showed an ill-definedmass in the posterior segment of the right upperlobe, the appearances of which were consideredto be those of a neoplasm. With this presumptivediagnosis, a right thoracotomy was performed inApril 1974. There were no adhesions but thevisceral pleura was thickened and there was a

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Necrotizing 'sarcoidal' angiitis and granulomatosis of the lung 3

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FIG. 1. Chest tomogram showing a poorly definedopacity in the right lateral lung field.

mass, approximately 5 cm in diameter, in theposterior segment of the right upper lobe closeto the posterior end of the horizontal fissure. Theoblique fissure was free except at its posterior endwhere the apical segment of the lower lobe wasfused to the posterior segment of the upper lobe.A right upper and middle lobectomy was per-formed.Examination of the excised specimen showed

that over the lateral surface of the upper lobethere was a densely fibrotic scar which extendedinto the lung to a depth of 2 cm at its centrepoint. It was wedge-shaped with its base abuttingon the pleural surface. About this scar there wasa cuff of pale tissue, 2 cm thick, with an irregularoutline (Fig. 2) but the main bronchi showed noevidence of tumour and elsewhere the lung ap-peared normal. The hilar lymph nodes measuredup to 1 cm in diameter.A preliminary histological examination showed

that the lung tissue about the scar containednumerous epithelioid and giant-cell granulomata(Fig. 3). No caseation was seen, but it was thoughtthat tuberculosis was the most likely of the manygranulomatous processes which might have pro-duced such changes. As the patient had thendeveloped a severe postoperative pneumonia hewas treated with antituberculosis chemotherapy.However, he failed to improve and when sputumculture demonstrated Haemophilus influenzae,ampicillin was added to the chemotherapy.Sputum and urine specimens showed no evidenceof tubercle bacilli on microscopy or subsequentculture, and no mycobacteria nor fungi werefound in specially stained sections of the resectedtissue.

Histological examination of further areas

FIG. 2. Part of the resected specimen showing acentral wedge-shaped scar surrounded by an ill-definedzone of pale inflammatory tissue.

showed abundant granulation tissue densely in-filtrated by lymphocytes and plasma cells inaddition to the many tuberculoid granulomaspreviously noted, and although the granulomaswere non-caseating there were a few foci ofnecrosis in the non-specific inflammatorygranulation tissue. These were walled off bydensely hyaline fibrous tissue (Fig. 4) and mayrepresent an older pre-existent lesion. A featureoverlooked on preliminary examination was in-volvement of blood vessels by the granulomatousprocess. Many medium-sized arteries and veinsshowed infiltration of their walls by lymphocytesand epithelioid and Langhans-type giant cells,sometimes forming focal granulomas (Fig. 5), butoften distributed more loosely within the vesselwall. All coats were involved and there wasfibrous thickening of the intima with narrowingor obliteration of the lumen. The lung tissue else-where appeared normal, and the hilar lymphnodes showed sinus histiocytosis only. No tumourwas found. The microscopic appearances werethought to correspond to those of NSG, and thiswas later confirmed by Dr. A. A. Liebow. Anti-tuberculosis therapy was therefore withdrawn. The

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FIG. 3. One of the many non-caseating 'sarcoidal'giant-cell granulomas. Haematoxylin and eosin (H andE X160).

patient made a steady recovery and was welland free from pain at follow-up two months later.

Six months after lobectomy the patient wasagain admitted to hospital with a three-day historyof increasing shortness of breath. On examinationhe was gravely ill, dyspnoeic at rest, and centrallycyanosed, and coarse crepitations were heardthroughout both lungs. An arterial blood gasdetermination showed a respiratory acidosis withhypoxaemia and hypercapnia (pH 7-23, Po2 62,Pco2 55 mmHg). A chest radiograph showedbilateral bronchopneumonia, and treatment withampicillin, 500 mg six-hourly, and hydrocortisone,200 mg six-hourly, was started. Within 20 hoursthe patient's condition improved dramatically,even though intensive physiotherapy had failed toproduce any sputum, and this suggested that hemay have been suffering from a recrudescence ofthe granulomatosis rather than pneumonia.A further radiograph showed considerable clear-

ing of the chest but a mass was now evident atthe left hilum. Biopsy of an enlarged cervicallymph node showed metastatic oat-cell carcinomaand it was assumed that the hilar mass wasneoplastic. Both hilar regions, mediastinum, and

FIG. 4. A necrotic focus surrounded by hyalinefibrous tissue (H and E X 160).

neck were irradiated (5400 rads over 25 days),following which his general condition remainedsatisfactory until two months after admissionwhen he deteriorated and died. At necropsy therewere hepatic metastases but in the lungs tumourwas limited to a small focus in the periphery ofthe left upper lobe. Elsewhere the lungs showeddiffuse interstitial fibrosis with hyaline membranesand a prominent alveolar epithelium compatiblewith radiation damage. Massive fibrosis withobliteration of the alveolar architecture, as foundin NSG, was not evident, and the appearancesprovided no support for a recrudescence of thisdisease.

DISCUSSION

Our 63-year-old man may be compared with the11 cases of NSG previously described by Liebow(1973) who were young or middle-aged, the oldestbeing 59 years, and of equal sex distribution. Twoof Liebow's patients, both with radiographicallylocalized unilateral disease, were asymptomatic,but most had symptoms such as cough, fever,sweats, malaise, dyspnoea, and pleuritic pain sug-gesting infection. The physical findings were

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Necrotizing 'sarcoidal' angiitis and granulomatosis of the lung

FIG. 5. A n artery showing discrete giant-cell granu-

lomas within its thickened walls (H and E X 125).

minimal, and there was no evidence of generalizeddisease. Chest radiographs generally showedmultiple nodules or ill-defined infiltrates but thetwo asymptomatic patients had localized disease,and our case would appear to correspond to these,the cough, wheezes, and sputum production beingattributable to chronic bronchitis.

Follow-up information available at present sug-gests that the course of NSG is relatively benignand that the disease is possibly responsive tosteroids. However, it is clear that when the pro-cess is localized the radiological appearances maylead to a presumptive diagnosis of carcinoma andsubsequent lung resection. Preliminary percutane-ous biopsy of all localized peripheral lung'tumours' would obviate some unnecessary lungresections. The histological characteristics are suchthat NSG may be confused with other granuloma-tous conditions, in particular sarcoidosis andtuberculosis. Familiarity with the condition willlead pathologists to pay particular attention tothe blood vessels, for, together with the sarcoidalgranulomas, angiitis is the hallmark of NSG. Thedefinite diagnosis will depend on histologicalexamination of an adequate biopsy specimen and

this may require thoracotomy. In view of theuncertain aetiology culture of the operativespecimen is also desirable.The aetiology of NSG is obscure and the pos-

sibility of a relationship to Boeck's sarcoidosisarises. Minute granulomas may be found in thehilar lymph nodes in NSG but there is no signifi-cant lymph node enlargement and extrapulmonary sites are not otherwise involved. Inpulmonary sarcoidosis the blood vessels are notusually affected, although vascular involvementwas prominent in the cases described by Bottcher(1959) and Michaels, Brown, and Cory-Wright(1960). In the first case described by Michaels andhis colleagues the process was confined to thelung, where it was associated with bronchiectasis.This patient possibly represents another case ofNSG. These authors speculate that thebronchiectasis may have played an aetiologicalrole in the development of the 'sarcoidosis', butin view of Liebow's description of airway involve-ment in NSG with consequent obstructivepneumonitis a reverse relationship is equallypossible. Other diseases which share morpholo-gical features with NSG include the limitedvariant of Wegener's granulomatosis distinguishedby its paucity of sarcoid lesions, and giant-cellarteritis distinguished by its anatomical distribu-tion and lack of surrounding chronic inflammatorygranulation tissue.

Boeck's sarcoid, Wegener's granulomatosis, andgiant-cell arteritis are widely differing diseases inwhich, though little is known of their aetiology,indeterminate immune disturbances are widelyfavoured. In NSG the presence of an angiitistogether with epithelioid and giant-cell granulo-mata is also very suggestive of hypersensitivityphenomena. A possibly immune process concen-trated on the lung suggests that an inhaled antigenmay have been the initiating factor but so far atleast in NSG none has been identified. Theassociation in our case with an oat-cell carcinomaof the opposite lung is probably coincidental buttumour antigens could conceivably have initiatedthe granulomatosis, just as they are suspected ofcausing renal glomerular damage (Higgins,Randall, and Still, 1974).

We are indebted to Professors A. A. Liebow and H.Spencer for advice on the histological diagnosis.

REFERENCES

Bottcher, E. (1959). Disseminated sarcoidosis with amarked granulomatous arteritis. Archives ofPathology, 68, 419.

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Carrington, C. B. and Liebow, A. A. (1966). Limitedforms of angiitis and granulomatosis of Wegener'stype. American Journal of Medicine, 41, 497.

Higgins, M. R., Randall, R. E., Jr., and Still, W. J. S.(1974). Nephrotic syndrome with oat-cell car-cinoma. British Medical Journal, 3, 450.

Katzenstein, A. L., Liebow, A. A., and Friedman, P. J.(1975). Bronchocentric granulomatosis, mucoidimpaction and hypersensitivity reactions to fungi.American Review of Respiratory Disease, 111,497.

Liebow, A. A. (1973). Pulmonary angiitis and granulo-matosis. A merican Review of Respiratory Disease,108, 1., Carrington, C. B., and Friedman, P. J. (1972).Lymphomatoid granulomatosis. Human Path-ology, 3, 457.

Michaels, L., Brown, N. J., and Cory-Wright, M.(1960). Arterial changes in pulmonary sarcoidosis.Archives of Pathology, 69, 741.

Wegener, F. (1936). Ober generalisierte septischeGefasserkrankungen. Verhandlungen der Deut-schen Gesellschaft fur Pathologie, 29, 202.

(1939). Uber eine eigenartige rhinogeneGranulomatose mit besonderer Beteiligung desArteriensystems und der Nieren. Beitrage zurpathologischen Anatomie und zur allgemeinenPathologie, 102, 36.

Requests for reprints to: Dr. B. Corrin, Departmentof Morbid Anatomy, St. Thomas' Hospital MedicalSchool, London SEI 7EH.

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